Abstract:

Process for the industrial synthesis of the compound of formula (I)
##STR00001##

Claims:

1. A process for the synthesis of a compound of formula (I) ##STR00005##
wherein (7-methoxy-1-naphthyl)acetonitrile of formula (II): ##STR00006##
is subjected to reduction by hydrogen in the presence of Raney nickel in
a medium comprising acetic anhydride in a polar protic medium to yield
the compound of formula (I), which is isolated in the form of a solid.

2. The process of claim 1, wherein the reaction is carried out under a
pressure of from 10 bars to 50 bars of hydrogen.

3. The process of claim 1, wherein the reaction is carried out at from
25.degree. C. to 90.degree. C.

4. The process of claim 1, wherein the amount of Raney nickel used in the
reaction is from 10% to 20% by weight.

[0003]It has, in fact, the double characteristic of being, on the one
hand, an agonist of receptors of the melatoninergic system and, on the
other hand, an antagonist of the 5-HT2C receptor. These properties
provide it with activity in the central nervous system and, more
especially, in the treatment of major depression, seasonal affective
disorder, sleep disorders, cardiovascular pathologies, pathologies of the
digestive system, insomnia and fatigue due to jet-lag, appetite disorders
and obesity.

[0004]Agomelatine, its preparation and its use in therapeutics have been
described in European Patent specifications EP 0 447 285 and EP 1 564
202.

[0005]In view of the pharmaceutical value of this compound, it has been
important to be able to produce it using an effective industrial
synthesis process which is readily transferable to the industrial scale
and which provides agomelatine in a good yield and with excellent purity.

[0006]Patent specification EP 0 447 285 describes production of
agomelatine in eight steps starting from 7-methoxy-1-tetralone, in an
average yield of less than 30%.

[0007]In Patent specification EP 1 564 202, the Applicant developed a new,
much more effective and industrialisable synthesis route in only four
steps that makes it possible to obtain agomelatine in highly reproducible
manner in a well-defined crystalline form.

[0008]The Applicant has now continued his investigations and developed a
new process for the synthesis of agomelatine that is even more effective
than that described in the prior art: agomelatine is obtained directly
starting from (7-methoxy-1-naphthyl)acetonitrile, which makes it possible
to achieve complete synthesis in only three steps starting from
7-methoxy-1-tetralone. This new process makes it possible to obtain
agomelatine in reproducible manner and without requiring laborious
purification, with a purity that is compatible with its use as a
pharmaceutical active ingredient.

[0009]Saving one or more steps in a synthesis process is always desirable
to industry because it allows a time saving, a gain in yield and,
consequently, a lower final cost. However, reducing the number of steps
in a synthesis procedure is not a trivial exercise, especially when
industrial quantities are involved: two steps combined into one involve
an increase in the number and amounts of reagents present and, owing to
the increased complexity of the mixture, purification of the reaction
product becomes more difficult. Finally, the probability of secondary
products appearing because of the greater number of reagents that are
present at the same time is very high.

[0010]The Applicant has now developed an industrial process which makes it
possible to obtain agomelatine directly, starting from
(7-methoxy-1-naphthyl)acetonitrile.

[0011]More specifically, the present invention relates to a process for
the industrial synthesis of the compound of formula (I):

##STR00003##

which process is characterised in that there is reacted
(7-methoxy-1-naphthyl)acetonitrile of formula (II):

##STR00004##

which is subjected to reduction by hydrogen in the presence of Raney
nickel in a medium comprising acetic anhydride in a polar protic medium
to yield the compound of formula (I), which is isolated in the form of a
solid.

[0012]The compound of formula (II) is obtained by customary reactions of
organic chemistry. The compound of formula (II) can, for example, be
obtained by condensation of cyanoacetic acid with 7-methoxy-tetralone
followed by oxidation of the condensation product, as described in Patent
specifications EP1564204 and EP1564205.

[0013]Preferably, conversion of the compound of formula (II) into the
compound of formula (I) according to the invention is carried out under a
minimum pressure of 5 bars and, more preferably, is carried out using a
pressure of from 10 bars to 50 bars of hydrogen.

[0014]Advantageously, conversion of the compound of formula (II) into the
compound of formula (I) according to the invention is carried out at from
25° C. to 90° C. and, more especially, from 50° C.
to 70° C.

[0015]The amount of Raney nickel used in the reaction converting the
compound of formula (II) into the compound of formula (I) is at least 5%
by weight and, more preferably, from 10% to 20% by weight.

[0016]The reaction medium for the reaction converting the compound of
formula (II) into the compound of formula (I) preferably comprises one or
more polar protic solvents such as ethanol, acetic acid and/or water, and
more preferably ethanol and/or water. Optionally, the reaction medium
additionally contains sodium acetate.

[0017]This process is especially valuable for the following reasons:
[0018]it makes it possible to obtain the compound of formula (I) on an
industrial scale in a single step, starting from
(7-methoxy-1-naphthyl)acetonitrile, in excellent yields of more than 85%;
this new process accordingly allows the compound of formula (I) to be
produced in only 3 steps starting from 7-methoxy-tetralone; [0019]the
compound of formula (I) obtained has, in reproducible manner, the
characteristics of the crystalline form described in Patent specification
EP1564202; [0020]the operating conditions that have been developed make
it possible to minimise formation of the major secondary product of the
reaction: N,N-bis[2-(7-methoxy-1-naphthyl)ethyl]acetamide, which
originates from dimerisation between two reaction intermediates; a priori
it was in fact very difficult--in view of the very existence of this
secondary reaction which dramatically increases in magnitude when the
reaction is carried out as a "one-pot" reaction--to envisage directly
obtaining the compound of formula (I) starting from
(7-methoxy-1-naphthyl)acetonitrile under purity conditions that are
compatible with its subsequent pharmaceutical use; lengthy and highly
detailed studies of the operating conditions were necessary in order to
arrive at an impurity level for the dimerised compound that is acceptable
for subsequent use of the compound of formula (I) as a medicament.

[0021]The Examples hereinbelow illustrate the invention but do not limit
it in any way.

EXAMPLE 1

N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide

Step A: (7-Methoxy-3,4-dihydro-1-naphthyl)acetonitrile

[0022]There are introduced into a 670 litre reactor 85.0 kg of
7-methoxy-1-tetralone, 60.3 kg of cyanoacetic acid and 15.6 kg of
heptanoic acid in toluene in the presence of 12.7 kg of benzylamine (or
11.0 kg of aniline). The mixture is heated at reflux. When all the
starting substrate has disappeared, the solution is cooled and filtered.
The precipitate obtained is washed with toluene and then the filtrate
obtained is washed with 2N sodium hydroxide solution and then with water
until neutrality. After evaporating off the solvent, the solid obtained
is recrystallised from an ethanol/water (80/20) mixture to yield the
title product in a yield of 90% and with a chemical purity of more than
99%.

Melting point: 48-50° C.

Step B: (7-Methoxy-1-naphthyl)acetonitrile

[0023]There are introduced into a 670 litre reactor 12.6 kg of 5%
palladium-on-carbon in toluene, which is heated at reflux; then 96.1 kg
of (7-methoxy-3,4-dihydro-1-naphthyl)acetonitrile dissolved in toluene
are added and also 63.7 kg of allyl methacrylate. The reaction is
continued at reflux and is monitored by vapour phase chromatography. When
all the starting substrate has disappeared, the reaction mixture is
cooled to ambient temperature and then filtered. After evaporating off
the toluene, the solid residue obtained is recrystallised from an
ethanol/water (80/20) mixture to yield the title product in a yield of
91% and with a chemical purity of more than 99%.

Melting point: 83° C.

Step C: N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide

[0024]There are introduced into an 8 litre reactor 136 g of Raney nickel,
2.06 litres of ethanol and 0.23 litre of water. Whilst stirring at
70° C. and under 30 bars of hydrogen, the compound obtained in
Step B (0.8 kg), dissolved in acetic anhydride (2.4 litres), is added
slowly. At the end of the addition, the reaction mixture is stirred for 1
hour under hydrogen at 30 bars; the reactor is then subjected to
decompression and the liquors are filtered. After concentrating the
mixture, the residue is crystallised from an ethanol/water 35/65 mixture
to yield the title product in a yield of 89% and with a chemical purity
of more than 99%.

Melting point: 108° C.

EXAMPLE 2

Determination of the Crystalline Form of the Compound
N-[2-7-methoxy-1-naphthyl)ethyl]acetamide Obtained in Example 1

[0025]Data recording was carried out using the D8 high-resolution
diffractometer from Bruker AXS with the following parameters: an angular
range of 3°-90° in terms of 2θ, a step of
0.01° and 30 s per step. The
N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide powder obtained in Example 1
was deposited on a transmission mounting support. The X-ray source is a
copper tube (λCuK.sub.α1=1.54056 Å). The mounting
includes a front monochromator (Ge(111) crystal) and an energy-resolved
solid-state detector (MXP-D1, Moxtec-SEPH). The compound is well
crystallised: the line width at half-height is of the order of
0.07° in terms of 2θ.

Determination, by Means of the X-ray Powder Diffraction Diagram, of the
Crystalline Form of the N-[2-7-methoxy-1-naphthyl)ethyl]acetamide
Compound Obtained in Example 1

[0033]The crystalline form of the compound obtained in Example 1 is
characterised by the following X-ray powder diffraction diagram, measured
using a Siemens D5005 diffractometer (copper anticathode) and expressed
in terms of interplanar distance d, Bragg's angle 2 theta, and relative
intensity (expressed as a percentage in relation to the most intense
line):